This invention relates to a method for transdermal administration of parathyroid hormone by iontophoresis, which comprises applying electric current with the mode of supply and non-supply intermittently, wherein the administration is repeated frequently every week.
Iontophoresis is a system for promoting transdermal administration with electricity. Its principle lies in promotion of transdermal administration of a drug molecule through a skin barrier based on forces with which a molecule usually positively charged with an electric current migrates from the anode to the skin in an electrolytic solution, while a negatively charged molecule migrates from the cathode to the skin (see Journal of Controlled Release, Vol. 18, 1992, p. 213-220; Advanced Drug Delivery Review, Vol. 9, 1992, p. 119 and Pharmaceutical Research, Vol. 3, 1986, p. 318-326).
Parathyroid hormone is clinically used as a diagnostic agent to test for the functioning of the parathyroid gland and is also being developed clinically as a promising drug for the treatment of osteoporosis. Drugs currently being used or developed clinically for the treatment of osteoporosis are classified into a group which suppresses bone resorption or into another group which promotes osteogenesis by increasing positively the bone mass.
Drugs for suppressing resorption of bone include calcitonin, bisphosphoric acid and estrogens. These drugs are applied to patients who are active in bone resorption to prevent or improve osteoporosis by reducing the amount of bone-loss through suppressing dissolution of calcium into blood. These drugs, however, do not have the effect of retrieving bone mass to its natural state, after the bone-loss. This is the most important goal in the treatment of osteoporosis. Therefore, these drugs are not expected to prevent fracture by increasing the bone mass in an osteoporotic patient whose bone mass has been greatly reduced.
On the other hand, drugs for promoting osteogenesis include vitamin K, fluorine preparations and hormones such as parathyroid hormone or bone morphogenetic protein (BMP) or growth hormones. Vitamin K and fluorine preparations have been clinically used but have not always produced excellent treatment results.
Parathyroid hormone has been known to promote bone resorption in addition to strongly promoting osteogenesis (D. W. Dempster et al, Endocrine Reviews, Vol. 14, 1993, p. 690). Therefore, in treating osteoporosis, it is important to utilize the hormone to produce only its osteogenic effect. For this purpose it may be significant to select a preferable mode of administration.
There are many reports, regarding the relationship between the administration mode and the effect of parathyroid hormone. It is recognized that intermittent injection is more effective for osteogenesis than administration methods where the hormone blood concentration is maintained for a long period of time (J. Reeve et al, J. Bone Miner. Res, Vol. 11, 1996, page 440). Therefore, from this point of view, clinical trials of the hormone have been conducted using repeated intermittent injections (R. Lindsay et al, Lancet, Vol. 350, 1997, p. 550).
Parathyroid hormone is a hormone secreted from the parathyroid glands. It is known that the hormone is secreted pulsatively at an interval of several tens minutes in a living body with normal functions. It also is known that in the living body, the blood hormone concentration is maintained as repetitions of pulsating blood concentrations which are far lower in peak values than what is obtained clinically by the usual injection of this hormone. Therefore, while avoiding side effects of the hormone, if the administration methods can make it possible to produce blood concentrations of parathyroid hormone as frequent pulses close to such natural secretion mode, it may be possible to increase bone mass. However, it is quite uncertain whether or not the bone resorption will interfere with the effect of the hormone produced by the administration method. In this connection, PCT International Patent Application Publication No. WO96/35447 discloses a way to increase the bone mass, if duration time in the blood of parathyroid hormone is set between 2 and 6 hours, preferably 4 hours in the above intermittent administration, as an administration mode for obtaining better therapeutic effects, as compared with a case of duration time of more than 6 hours (for example 8 hours) or a 1 hour or bolus administration of lesser duration time.
Generally, the treatment of osteoporosis needs administration of drugs over a long period of time, from several months to several years. From this point of view, a self-administration is preferable. With oral administration which is one possible self-administration method, parathyroid hormone is poorly absorbed through digestive mucous membranes, because it is poorly permeable through mucous membranes and is also degraded by enzymes in the digestive tract because it is a peptide. With other possible self-administration methods, there may be mentioned intranasal or transpulmonary administration. In order to attain desired absorption of a drug, these administration routes need addition of an enzyme inhibitor or a stimulative agent for promoting permeability through mucous membrane. Even using these administration methods, it is necessary to administer the hormone as many times as the number of desired pulses in order to produce blood pulsatile parathyroid hormone concentration. It is practically impossible to repeat such administrations at intervals of, for example, tens minutes or several hours during the long periods of treatment.
As another self-administration method, percutaneous administration is considered. Generally, absorption of a peptide in usual percutaneous administration is extremely low even with the use of an agent for promoting absorption or other additives, and, therefore, such an administration method would not be practical. Also, a usual percutaneous administration could not produce blood concentrations of multiple pulse type in a one time administration.
European Patent Application Publication No. 747092 discloses percutaneous administration of thyroid hormone by iontophoresis. This method makes it possible for parathyroid hormone to penetrate skin barrier (mainly stratum corneum) through which the hormone usually could not penetrate, depending on electric current. In the publication, it is described that the total of current application time is preferably not longer than 24 hours, more preferably about not longer than 12 hours and particularly not longer than 6 hours.
However, nothing has been known from the view point of side effects and pharmacological effects, as to the appropriate frequency of administration of electric current in long term administration of parathyroid hormone by iontophoresis.
This invention relates to a method for transdermal administration of parathyroid hormone by iontophoresis, which comprises applying electric current with the mode of supply and non-supply intermittently, wherein the administration is repeated frequently every week.